Amide-Forming Ligations at Physiological pH for the Encapsulation of Human Mesenchymal Stem Cells

The development of rapid, chemoselective covalent bond-forming reactions enables the assembly of hydrogel scaffolds suitable for applications in cellular encapsulation. We previously reported that amide-forming ligations between potassium acyltrifluoroborates (KATs) and hydroxylamines produce robust hydrogels that have excellent cytocompatibility, but the requirement for somewhat acidic conditions for efficient hydrogel assemblies limited their application to robust cell types. To overcome this constraint, we have recently found that quinolinium acyltrifluoroborates (QATs) serve as highly efficient reaction partners for amide-forming reactions at neutral pH. In this article, we document the construction of poly(ethylene glycol) (PEG)-derived hydrogels by efficient cross-linking of QAT-functionalized macromers with a partner hydroxylamine-functionalized macromer. Gelation occurs at physiological pH in under 2 min, offering a rapid and facile approach to the immobilization of delicate stromal cells. The cytocompatibility of the cross-linking was demonstrated by <i>in situ</i> gelation in the presence of human mesenchymal stem cells and sustained cell viability for 7 days. Facile incorporation of a cyclic cell adhesion peptide, simply by including the reaction partner in the gelation reactions, illustrated that the desired components can be introduced into the gels without further elaboration.